" NON INVASIVE ASSESSMENT OF CORONARY FLOW VELOCITY RESERVE WITH TRANSTHORACIC COLOUR DOPPLER ECHOCARDIOGRAPHY TO PREDICT SIGNIFICANT LEFT ANTERIOR

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1 " NON INVASIVE ASSESSMENT OF CORONARY FLOW VELOCITY RESERVE WITH TRANSTHORACIC COLOUR DOPPLER ECHOCARDIOGRAPHY TO PREDICT SIGNIFICANT LEFT ANTERIOR DESCENDING CORONARY ARTERY STENOSIS ". Dissertation Submitted to THE TAMIL NADU DR.M.G.R. MEDICAL UNIVERSITY In partial fulfillment of the regulations For the award of the degree of DM BRANCH-II CARDIOLOGY GOVT. STANLEY MEDICAL COLLEGE & HOSPITAL, CHENNAI. THE TAMIL NADU DR.M.G.R. MEDICAL UNIVERSITY CHENNAI. AUGUST 2007

2 CERTIFICATE This is to certify that the dissertation entitled " NON INVASIVE ASSESSMENT OF CORONARY FLOW VELOCITY RESERVE WITH TRANSTHORACIC COLOUR DOPPLER ECHOCARDIOGRAPHY TO PREDICT SIGNIFICANT LEFT ANTERIOR DESCENDING CORONARY ARTERY STENOSIS " is the bonafide original work of Dr.K.TAMILSELVAN, in partial fulfillment of the requirements for D. M. Branch-II (CARDIOLOGY) Examination of the Tamilnadu Dr.M.G.R. Medical University to be held in August PROFESSOR R.SUBRAMANIAN, MD, DM., Professor and Head, Department of Cardiology, Government Stanley Medical College & Hospital, Chennai. DEAN GOVERNMENT STANLEY MEDICAL COLLEGE & HOSPITAL CHENNAI.

3 DECLARATION I, DR.K.TAMILSELVAN, solemnly declare that the dissertation titled "NON INVASIVE ASSESSMENT OF CORONARY FLOW VELOCITY RESERVE WITH TRANSTHORACIC COLOUR DOPPLER ECHOCARDIOGRAPHY TO PREDICT SIGNIFICANT LEFT ANTERIOR DESCENDING CORONARY ARTERY STENOSIS the bonafide original work done by me at Government Stanley Medical College and Hospital during May 2006 to May 2007 under the guidance and supervision of PROF.R.SUBRAMANIAN, MD, DM. Professor and Head Of the Department. This dissertation is submitted to The Tamilnadu DR.M.G.R. Medical University, towards partial fulfillment of the requirements for D. M. Branch-II (CARDIOLOGY) Examination to be held in August 2007 Place: Chennai Date: (Dr.K.TAMILSELVAN)

4 ACKNOWLEDGEMENT At the outset, I wish to express my respect and sincere gratitude to my beloved teacher PROF.R.SUBRAMANIAN, M.D., D.M., (Cardiology) Professor & HOD, Department of Cardiology, for his valuable guidance and encouragement throughout the study. I am extremely thankful to our Additional Professor DR.M.SOMASUNDARAM, M.D., D.M (Cardiology) for his support and guidance during the study. I am grateful to DR.M.S.RAVI,M.D.D.M.,DR.R.N.ANNAMALAI,M.D.D.M., DR.K.KANNAN,M.D.D.M., DR.M.NANDAKUMARAN,M.D.D.M., DR.R.SIVAN,M.D..D.M., DR.ASHOKVICTOR,M.D.D.M.,DR.P.M.NAGESWARAN,M.D.D.M., Assistant Professors of Cardiology for their moral and technical support during the study. I thank DR.T.RAVEENDRAN, M.D.(CHEST), DTCD., DEAN,Government Stanley Medical College, Chennai for permitting me to utilise the hospital materials for conducting this study. I express my thanks to Mr.A.Venkatesan, Lecturer in Statistics, clinical epidemiology unit, Government Stanley Medical College for his help in statistical analysis. Last but not the least, I thank all the patients who ungrudgingly lent themselves to undergo this study without whom this study would not have seen the light of the day.

5 CONTENTS PAGE NO: 1. INTRODUCTION 1 2. AIM 2 3. REVIEW OF LITERATURE 3 4. MATERIALS AND METHODS RESULTS AND DATA ANALYSIS DISCUSSION CONCLUSION BIBILIOGRAPHY PROFORMA GLOSSARY 61

6 INTRODUCTION Definite diagnosis of coronary occlusion can be made by coronary angiography (CAG). However, it is an invasive technique and only available in the catheterization laboratory. Patients without anginal symptoms, left ventricular dysfunction or electrocardiographic changes may not be diagnosed until cardiac events occur. If noninvasive detection of total coronary occlusion before CAG becomes possible, it could help in the consideration of further invasive procedures and in the estimation of the results of various interventions. Coronary flow velocity measurements have provided useful clinical and physiologic information. They have been assessed by several Doppler techniques with a Doppler catheter, a Doppler guidewire, an epicardial probe and a transesophageal probe. Doppler catheter and a Doppler guidewire are already have been validated for the measurement of Coronary flow velocity and established as useful techniques in the clinical setting. However, they are invasive.. Transesophageal Doppler echocardiography is semiinvasive,. Thus, it has been difficult to apply assessment of CFV to patients in routine clinical practice. Transthoracic Doppler echocardiography is noninvasive, relatively inexpensive and widely used in the clinical setting, and can be used for serial studies in echocardiographic laboratories. Several studies have reported that CFV can be measured by visualizing LAD using transthoracic two-dimensional and Doppler echocardiography with a high-frequency transducer. It has been also shown that CFV in the distal LAD can be measured at high success rate by TTDE under the guidance of color Doppler flow mapping, and assessment of CFVR in the LAD by this noninvasive technique is useful in the diagnosis of significant LAD stenosis.

7 AIM To determine whether the coronary flow velocity pattern assessed by Transthoracic Colour Doppler Echocardiography serves as a predictor of significant Left Anterior Descending coronary artery stenosis. To evaluate the value of coronary flow velocity reserve determined by Transthoracic Colour Doppler Echocardiography for the assessment the degree of severity of Left Anterior Descending coronary artery stenosis. To compare coronary flow velocity pattern assessed by Transthoracic Colour Doppler Echocardiography and Exercise stress testing with Treadmill to predict significant Left Anterior Descending coronary artery stenosis.

8 REVIEW OF LITERATURE Atherosclerotic coronary stenosis is the most common cause of myocardial ischemia. Based on data from the Framingham Heart Study, the lifetime risk of developing symptomatic CAD after age 40 is 49 percent for men and 32 percent for women. Ischemic heart disease is now the leading cause of death worldwide. The World Health Organization estimates that by 2020 the global number of deaths from CAD will have risen from 7.1 in 2002 to 11.1 million 1. Different clinical ischemic syndromes result from fixed obstruction to coronary blood flow by atherosclerotic plaques or thrombosis,or by abnormal epicardial coronary vasomotion,or by microvascular dysfunction. These events can occur together or separately. Understanding the coronary circulatory physiology aids physicians to diagnose and treat these events effectively. DIAGNOSIS OF CORONARY ARTERY DISEASE Definite diagnosis of coronary stenosis can be made by coronary angiography (CAG). However, it is an invasive technique and only available in the catheterization laboratory. Patients without anginal symptoms, left ventricular dysfunction or electrocardiographic changes may not be diagnosed until cardiac events occur. If noninvasive detection of coronary stenosis before CAG becomes possible, it could help in the consideration of further invasive procedures and in the estimation of the results of various interventions. Many noninvasive methods like Exercise stress testing, Stress Echocardiography, Nuclear imaging and CT angiography can aid in prediction of coronary stenosis.each has different sensitivity and specificity to predict coronary stenosis in relation to stenosis diagnosed by coronary angiogram as a gold standard investigation.

9 ANGIOGRAPHIC ASSESSMENT OF CORONARY ARTERY NARROWINGS: An angiographic lumen narrowing is commonly referred to as a stenosis which may be due to atherosclerosis, vasospasm, or angiographic artifact. To quantify the coronary stenosis accurately it must be seen in profile, free from artifact related to foreshortening or obfuscation by a crossing vessel. Multiple views are important, because many lesions have a markedly eccentric lumen. When seen across its major axis, the width of the lumen may appear to be normal, but a clue to the presence of a severe degree of narrowing in the other axis may be marked lucency caused by thinning of the contrast column. The normal caliber of major coronary arteries, Left main 4.5±0.5mm,LAD 3.7±0.4mm, LCX 3.4±0.5mm for non dominant and dominant LCX 4.2 ±0.6mm; RCA 3.9 ± 0.6 for dominant and 2.8 ± 0.5 for non dominant. By comparing the diameter of a presumably disease free segment of coronary artery to the size of the diagnostic catheter (6F equals 2mm), the operator can identify vessels that fall below these normal size ranges and may thus be diffusely diseased. The evaluation stenosis relates to the percentage of reduction in the diameter of narrowed vessel site to the adjacent unobstructed vessel. The diameter stenosis is calculated in the projection where the greatest narrowing is seen. It should be noted that the stenotic lumen is compared to near by unobstructed lumen, which indeed may have diffuse atherosclerotic disease and thus is angiographically normal but still may be diseased. The area of stenosis is always greater than diameter stenosis and assumes the lumen is circular when in reality most of the time the lumen is eccentric. A 50 % of reduction in diameter is equivalent to a 75% reduction in Cross Sectional area, and a 75% reduction diameter is equal to a 90 % reduction in cross sectional area. Stenosis that reduces the lumen diameter by 50% (and hence cross sectional area by 75%) is hemodynamically significant, in that it reduces the normal three fold to four fold flow reserve of coronary bed. Whereas a diameter stenosis of 70% (90% cross sectional area) eliminates virtually any ability to

10 increase flow above it's resting level. Stenosis that reduced the lumen diameter by 90%, however, rarely exists without reducing antegrade flow. Because of the subjective nature of a visual lesion assessment, there is a ± 20% variation between readings of two or more experienced angiographers especially for lesions 40 70% narrowed. The simplest way to resolve this problem is, project the coronary image on a wall mounted viewing screen, and use inexpensive digital calipers to measure the relative diameters of the stenotic and reference segment. Percent stenosis can be calculated as 100 (1 stenosis diameter/reference diameter) to provide a more accurate estimate of stenosis. TIMI FRAME COUNT Myocardial blood flow has been assessed angiographically using Thrombolysis in Myocardial infarction (TIMI) score for qualitative grading of coronary flow. TIMI flow grades 0 3 have become a standard description of angiographic coronary blood flow in clinical trails. Quantitative method of TIMI uses cine angiography with 6F catheters and filming at 30 frames per second.the number of cine frames from the introduction of dye in the coronary artery to predetermined distal landmark is counted. The first frame used for TIMI frame counting is that in which the dye fully opacifies the artery origin and in which the dye extends across the width of the artery touching both borders with anterograde motion of the dye. The last frame counted is when the dye enters the first landmark branch. Full opacification of distal branch not required. The distal landmark commonly used in analyses are, (1) for LAD -the distal bifurcation of LAD. (2) for the circumflex system,the distal bifurcation of branch segments with the longest total distance. (3) for the RCA the first branch of posterolateral artery. The TIMI frame count can further be quantified for the length of the LAD for comparison to the two other major arteries. This is called corrected TIMI frame count (CTFC). The average LAD coronary artery is 14.7cm long, RCA 9.8cm, LCX 9.3cm. CTFC accounts for the distance the dye has to travel in

11 the LAD relative to the other arteries. CTFC divides the absolute frame count in LAD by 1.7 to standardise the distance of dye travel in all the three arteries. Normal TFC for LAD is 36±3 and CTFC 21±2, for LCX TFC is 22±4, for RCA TFC is 20±3. TIMI flow grades do not correspond to measured Doppler flow velocity or CTFC. High TFC may be associated with microvascular dysfunction despite an open artery. CTFC of <20 frames were associated with low risk for adverse events in patients following myocardial infarction. A contrast injection rate of >1ml/sec by hand injection can decrease the TIMI frame count by 2 frames. The TIMI frame count method provides valuable information relative to clinical responses after coronary intervention. COLLATERAL CIRCULATION The reopacification of a totally or subtotally (99%)occluded vessel from antegrade or retrograde filling is defined as collateral filling... Angiographically visible collateral channels are not usually seen until the coronary obstruction is greater than 90%, at which point coronary perfusion pressure falls substantially and the blood flow through the collaterals increases.the collateral circulation may provide upto 50% of anterograde coronary flow in chronic total occlusions. PHYSIOLOGY OF CORONARY CIRCULATION: The flow through the coronary arteries is pulsatile, with characteristic phasic systolic and diastolic flow components. Systolic compression of the intramural coronary vessels causes mean systolic arterial flow to be reduced relative to diastolic flow, despite having a higher systolic driving pressure. The systolic flow wave has rapid, brief retrograde responses corresponding to phasic myocardial compliance over the cardiac cycle. Diastolic flow occurs during the relaxation phase after myocardial contraction with an abrupt increase above systolic levels and a gradual decline parallel with that of aortic diastolic pressure.the coronary blood flow not only is phasic but also varies with the type of vessel and location in the myocardium.

12 A system of multiple functional "valves" permits fine control of the coronary circulation. The smallest arterioles dilate during metabolic stress, resulting in reduced microvascular resistance and increased myocardial perfusion. As the upstream arteriolar pressure decreases owing to a fall in distending pressure across a stenosis, myogenic dilation of slightly larger arterioles upstream occurs and causes an additional decrease in resistance. Increased flow in the largest arterioles augments shear stress and triggers flow-mediated dilation, further reducing the resistance of this network. Thus, coronary arterioles appear to have specialized regulatory elements along their length that operate "in series" in an integrated manner. INFLUENCE OF A STENOSIS ON CORONARY BLOOD FLOW Resistance to flow changes exponentially with lumen cross-sectional area and linearly with lesion length. Additional factors contributing to resistance include the shape of the entrance and exit orifices, vessel stiffness, and distensibility of the diseased segment (permitting active or passive vasomotion) and the variable lumen obstruction that may be superimposed by platelet aggregation and thrombosis compromising lumen area, a process active in acute coronary syndromes. The physiological effect of a coronary stenosis also depends on the degree to which the resistance to flow can be compensated by dilation of the microcirculation distal to the stenosis. Resting coronary flow is not impeded by mild or moderate stenoses and is maintained by normal vasodilatory regulation of the microcirculation. Resting coronary blood flow remains constant up to the point where an epicardial coronary constriction exceeds 85 to 90 percent of the normal segment diameter.however, unlike resting flow, maximal hyperemic coronary blood flow begins to decline when diameter stenosis exceeds 45 to 60 percent. The capacity to increase coronary blood flow in response to a hyperemic stimulus, called

13 coronary flow reserve (CFR), is abolished when diameter stenosis exceeds 90 percent. CORONARY PRESSURE AND FLOW FOR THE PHYSIOLOGICAL ASSESSMENT OF A CORONARY STENOSIS The hemodynamic significance of a given stenosis in humans can be measured by the pressure-flow relationship using sensor angioplasty guidewires. Three types of stimuli have been used to elicit maximal coronary blood flow in humans: (1) transient coronary occlusion during angioplasty (reactive hyperemia); (2) pharmacological vasodilators; and (3) metabolic stress Reactive hyperemia follows an occlusion as short as 200 milliseconds. Maximal reactive hyperemia follows coronary occlusion of 20 seconds. Longer occlusion increases the duration but not the amplitude of the hyperemic response. At maximal hyperemia, autoregulation is also abolished and coronary blood flow is directly related to the driving pressure. Adenosine, dipyridamole, and papaverine are the principal pharmacological vasodilators used to elicit coronary hyperemia. CORONARY FLOW RESERVE (CFR) CFR is defined as a ratio of maximal to baseline (resting) coronary blood flow.. CFR measurement is used both to assess epicardial coronary stenoses and to examine the integrity of micro vascular circulation.. In the absence of stenosis in epicardial coronary artery,the CFR may be decreased when coronary micro vascular circulation is compromised by arterial hypertension with or without left ventricular hypertrophy, diabetes mellitus, hypercholesterolemia, syndrome X, hypertrophic cardiomyopathy or other diseases 1. METHODS TO ASSESS CFR CFR measures the ability of the two components of myocardial perfusion, namely the epicardial stenosis resistance and the microvascular resistance, to achieve maximal blood flow.

14 There are two invasive methods available to measure coronary blood flow in the catheterization laboratory: intracoronary Doppler flow velocity and coronary thermodilution. Volumetric flow is the product of vessel area (square centimeters) and flow velocity (centimeters per second) yielding a value in cubic centimeter per second. The coronary thermodilution technique uses thermistors on a pressure-sensor angioplasty guidewire and measures the arrival time of room temperature saline bolus indicator injections through the guiding catheter into the coronary artery. When combined with poststenotic pressure measurements, CFR measurements can provide a complete description of the pressure-flow relationship and the response of the microcirculation. Normal CFR in young patients with normal arteries by intravascular ultrasound commonly exceeds 3.0. In patients with chest pain undergoing cardiac catheterization with angiographically normal vessels, the CFR averages 2.7 ± 0.6. Tachycardia increases basal flow, reducing CFR. Increasing mean arterial pressure reduces maximal vasodilation, reducing hyperemic flow more than basal flow. CFR may be reduced in patients with normal coronary arteries who have essential hypertension or aortic stenosis. Diabetes mellitus also reduces CFR, especially in patients with diabetic retinopathy Several methods have been established for measuring CFR. However, these methods are either invasive (intracoronary Doppler flow wire), highly expensive and scarcely available (Positron Emission Tomography) or semiinvasive and scarcely feasible (transesophagealdoppler), thus their clinical use is limited. In addition, PET and intracoronary Doppler flow wire involve radiation exposure, with inherent risk, environmental impact and biohazard connected with use of ionizing testing.

15 NONINVASIVE ASSESSMENT OF CORONARY FLOW VELOCITY RESERVE WITH TRANSTHORACIC COLOR DOPPLER ECHOCARDIOGRAPHY Transthoracic coronary Doppler ultrasound turns our attention from surrogate markers of atherosclerosis, such as brachial/ankle index, left ventricular mass, and carotid intima/media thickness to a direct screening modality of coronary flow THE WINDOW Coronary blood flow velocity should be measured from an apical window by pulsed Doppler ultrasound under colour-coding guide. The best long axis view in colour flow imaging should be obtained to maintain a <30 degree angle between flow and the Doppler beam. Correction for the theta angle may be used,5 7 but it is a redundant operation, since CFVR is not an absolute, but a derived value (ratio between hyperaemic and baseline coronary blood flow velocity). METHODOLGY. The TTDE examinations were performed with color Doppler flow mapping, the velocity range was set at ±9.6 to 28.8 cm/s. The color gain was adjusted to provide the optimal images. The transducer was placed at the fourth or fifth intercostal space the cardiac apex and the parasternal area the anterior interventricular groove was visualized in the short-axis view.,. In the short-axis images of the left ventricle, the mid-portion of the LAD can be identified as a cross section of the tubular structure containing the color Doppler flow signal, positioned in the anterior interventricular sulcus.. After confirming its position, the transducer was rotated counterclockwise to visualize the LAD, which runs along the interventricular sulcus, in the long-axis section while color Doppler flow with a Nyquist limit of ±19 to ±24 cm/s was applied to visualize the LAD flow with relatively low velocity; After positioning a sample volume (1.5 to 2.5 mm wide) on the color signal in the LAD, Doppler spectral tracings of flow velocity were recorded by the pulsed Doppler method. Transducer position and direction were adjusted to make the Doppler beam as parallel as possible to LAD flow, and an angle

16 correction was performed Angle correction was needed in each examination (incident angle 41 ± 11 ). All studies were recorded on s-vhs videotape. Using the computer analysis system incorporated in the ultrasound system, off-line measurements of mean diastolic velocities and peak diastolic velocities were performed by tracing the contour of the spectral Doppler signal. Flow velocity recordings were performed in a stable transducer position at rest and during maximal hyperemia, which was induced by intravenous administration of adenosine (140µg/kg/min). Systolicdiastolic average peak velocities at rest and during maximal hyperemia (mean peak velocity) were used for off-line analysis of spectral Doppler tracings to calculate CFR. The values of three consecutive beats were averaged to calculate the flow velocity at rest and during hyperaemia. When the distal LAD flow was retrograde by color Doppler or was not visualized within 5 minutes, antegrade LAD flow was considered to be absent, and the TTDE coronary study was discontinued The sampling site is critical for correct coronary flow measurements because the results may be very different when CFVR is measured proximal to the stenosis, at the level of the stenosis or distal to it. Proximal to the stenosis, CFVR may be perfectly normal, as it reflects perfusion in normal territories. It may be altered only in the rare case there are no side branches between the sampling site and the stenosis. This is one of the reasons why transoesophageal echocardiography, which allows imaging of the left main and the very initial tract of the LAD, has been abandoned for the study of CFVR in CAD. At the level of the stenosis, baseline coronary flow accelerates to cm/s or more to compensate for lumen loss and maintain the coronary output constant. This accelerated baseline flow prevents reliable calculation of CFVR. Coronary flow should therefore be measured at the distal tract of the coronary artery for three reasons, (1) The effect of flow acceleration from a proximal or mid coronary stenosis is minimal (2) The cumulative effect of sequential stenoses can be assessed,

17 because all end in alteration of distal flow; (3) Compared to the proximal and middle tract of the coronary artery, the capacitance of the distal tract is minimal, and changes in velocity best reflect changes in vital, intramural flow.24 BASELINE FLOW VELOCITY Myocardium can incur only a small oxygen debt, and myocardial oxygen consumption is strictly flowdependent. For this reason, baseline coronary blood flow may be readjusted on a beat-by-beat basis, and baseline coronary flow velocity may change from one beat to the other of even 5 10 cm/s. It is therefore important, in case of significant variability of baseline flow velocities, to average values obtained from at least three beats, in order to prevent misinterpretations. Elevated resting flow velocities may occur in several cardiac and non-cardiac conditions increasing oxygen consumption at rest, including tachycardia, anaemia,hyperthyroidism, severe left ventricular hypertrophy, valvular diseases, etc. On the other hand, coronary vasodilators such as nitrates or calcium antagonists increase the diameter of the epicardial artery and reduce baseline flow velocity. B-Blockers may also reduce baseline coronary flow velocity, mainly by decreasing heart rate and blood pressure, and hence oxygen consumption. Adenosine and Doppler Hyperaemic flow is obtained by venous infusion of adenosine (140 lcg/kg/min), a pure and strong dilator of the coronary microcirculation, having little or no effect on the epicardial artery. ADENOSINE Adenosine, the most commonly used agent in the catheterization laboratory, can be administered by the intravenous or intracoronary route. RF Wilson et al investigated in humans the effects of adenosine, administered by intracoronary bolus (2-16 micrograms), intracoronary infusion ( micrograms/min), or

18 intravenous infusion ( micrograms/kg/min) on coronary and systemic hemodynamics and the electrocardiogram. Coronary blood flow velocity (CBFV) was measured with a 3F coronary Doppler catheter. Intracoronary infusions of 80 micrograms/min or more into the left coronary artery also caused maximal hyperemia, and doses up to 240 micrograms/min caused a minimal decrease in arterial pressure (-6 +/- 2 mm Hg) and no significant change in heart rate or in electrocardiographic variables. Intravenous infusions in normal patients at 140 micrograms/kg/min caused coronary vasodilation similar to that caused by papaverine. At submaximal infusion rates, however, CBFV often fluctuated widely. During the 140-micrograms/kg/min infusion, arterial pressure decreased 6 +/- 7 mm Hg, and heart rate increased 24 +/- 14 beats/min.. MJ Kern et al showed that coronary blood flow velocity were measured at rest and during peak hyperemic responses to continuous intravenous adenosine infusion (50, 100 and 150 micrograms/kg per min for 3 min) and intracoronary papaverine (10 mg) and after low dose (2.5 mg) intravenous bolus injection of adenosine. The maximal adenosine dose did not change mean arterial pressure but increased the heart rate.... Intracoronary boluses caused a small, brief decrease in arterial pressure (similar to that caused by papaverine) and no changes in heart rate or in the electrocardiogram. The duration of hyperemia was much shorter after adenosine than after papaverine administration.. Low dose bolus injection of adenosine increased mean velocity equivalently to that after continuous infusion of 100 micrograms/kg, but less than after papaverine. There was a strong correlation between adenosine infusion and papaverine for both mean coronary flow velocity and coronary vasodilator reserve ratio. No patient had significant arrhythmias or prolongation of the corrected QT (QTc) interval with adenosine, but papaverine increased the QT (QTc) interval. Adenosine is benign in the appropriate dosages (20 to 30 µg in the right coronary artery or 30 to 50 µg in the left coronary artery or infused intravenously at 140 µg/kg/min). Intravenous dobutamine (10 to 40 µg/kg/min) can also produce maximal hyperemia without modifying the angiographic area of

19 the epicardial stenosis. Coronary flow is the product of velocity and the cross-sectional area of the vessel. Because the diameter of the epicardial artery does not change significantly during adenosine infusion, velocity can be used as an acceptable surrogate of flow. This is an important prerequisite for any drug used to study CFVR, because according to the Poiseuille s law, even small variations in calliper may cause large variations in velocities and hence in flow. Compared to dipyridamole, adenosine is more potent and more versatile, as it can be repeatedly infused just after coronary flow velocity returns to baseline. SAFETY It is better to infuse adenosine for no more than 90 s, for three main reasons: (1) the maximal hyperaemic effect is already reached at s; (2) short infusion times prevent the development of myocardial ischaemia, which may occur for more prolonged infusion; (3) the costs are significantly reduced. Small bolus injection is safe and effective. The adenosine dose may actually be reduced to a minimum of 2.5 mg bolus injection, which produces an increase in CFVR similar to that obtained by 3 min venous infusion, and has no significant side-effects,40 with important practical and economical implications. According to Voci et al, in his series of more than 1000 patients studied with either short infusion or bolus injection, including those with acute coronary syndromes, there was only one episode of transient atrial fibrillation in a patient with poor left ventricular function and recurrent episodes of paroxysmal atrial fibrillation. Nevertheless, some authors still use infusion times of up to 5 6min, which may cause significant side-effects, and may result in myocardial ischaemia in critical patients 5 7. IS THERE A ROLE FOR SYSTOLE? It may be difficult to record both diastolic and systolic flow in the same cardiac cycle in all patients, because rotational and translational movements of the heart displace the coronary artery from the ultrasound beam in systole. However, compared to the diastolic, systolic flow is a less important and

20 less stable measure. Diastolic flow is anterograde in both epicardial and intramural vessels, whereas systolic flow is anterograde in epicardial but retrograde in intramural vessels, where blood is squeezed backwards by myocardial contraction. As a result of the two opposite forces, the magnitude of systolic flow velocity may change along the coronary tree and close to the origin of a perforator there might be a watershed area with stagnation of systolic flow. 16 Therefore, the epicardial anterograde systolic flow is mainly a capacitance, rather than a nutrient flow, and does not reflect myocardial perfusion. DIAGNOSIS OF SIGNIFICANT CORONARY STENOSIS: CFVR reflects the impact on total coronary resistances of: (1) The patency of the epicardial coronary artery, and (2) The vasodilator capacity of the microcirculation. In normal coronary arteries, CFVR entirely describes the resistances of the microcirculation. A flowlimiting stenosis introduces a strong proximal resistance that is higher than that opposed by the microcirculation, as demonstrated by the early normalization of CFVR after the mechanical relief of the stenosis by coronary stenting.11 Therefore, the impact of microcirculation on CFVR is of secondary importance, compared to that of a significant epicardial stenosis. Lance Gould established in his seminal experimental work that a CFVR of 2 discriminates significant (P70%) from non-significant (<70%) coronary stenoses. 28,29. Human studies using single photon emission computed tomography 30 and intracoronary 45 and transthoracic coronary Doppler ultrasound 3 8, have confirmed these findings, and a cut-off value of 2 has been widely adopted as the magic number discriminating significant impairment of coronary flow that should be treated invasively by mechanical removal of the stenosis. Translated into clinical practice, transthoracic coronary Doppler ultrasound helps deferring revascularization in patients with CFVR above 2, with important economical, ethical and

21 social implications. In keeping with the experimental findings, transthoracic coronary Doppler ultrasound correlates well with the angiographic degree of the stenosis. 3 8, This is true for nonsignificant (<50%) and significant (P70%) coronary lesions, but data on intermediate (50 69%) lesions 10 are more dispersed. This is not surprising, since intermediate lesions are difficult to quantify even with quantitative coronary angiography, which in fact cannot reliably predict the physiological impact of these stenoses. In intermediate stenoses, coronary Doppler ultrasound may guide our clinical decision making, reserving percutaneous coronary interventions only to patients with reduced CFVR. 47. Transthoracic coronary Doppler ultrasound has several advantages over other stress tests: (1) It is accurate in detecting single vessel disease, 17,19 However, with the currently available technology, transthoracic coronary Doppler ultrasound cannot detect branch stenosis; (2) It is less time consuming, because theoretically only few baseline and hyperaemic diastoles are needed to measure CFVR; (3) It provides a quantitative measure of coronary blood flow, which is particularly useful for follow-up evaluation; 13 (4) It is independent of baseline ST alterations and bundle branch block; (5) Drugs such as b-blockers may not be discontinued. 35 INTERMEDIATE STENOSIS Understanding the functional impact of stenosis is important for clinical decision making. One example is whether to refer or defer patients with intermediate stenosis for percutaneous transluminal coronary angioplasty (PTCA).CFR measured distal to the stenosis precisely defines the hemodynamic significance of stenosis. In studies using transthoracic Doppler echocardiography, CFR <2 is associated with stress-induced ischemia and reduced CFR is considered as a manifestation of

22 functionally important stenosis even if coronary angiography reveals intermediate severity In contrast, patients with intermediate stenosis but with adequate CFR value, PTCA can be safely deferred. The measurement of CFR by transthoracic Doppler echocardiography provides data equivalent to those obtained by thallium-201 scintigraphy for physiologic estimation of the severity of LAD stenosis. CRITICAL LAD STENOSIS: The Coronary Artery Surgery Study registry states that patients with >90% stenosis have a times higher probability to develop acute myocardial infarction than those with less severe lesions. Unfortunately, neither the clinical presentation, nor the currently available non-invasive tests can reliably discriminate severe from non-severe stenosis. Using transthoracic Doppler echocardiography, it is possible to detect severe LAD stenosis >90%. The CFR <1, which suggests coronary steal may be a predictor of critical coronary stenosis 23. Coronary steal is defined as a decrease of CFR to a certain vascular region in favor of another area during maximal coronary vasodilatation, that is, CFR <1. Lance Gould showed that the hyperaemic response disappears at 90% vessel stenosis. 37,38 a damped CFVR during adenosine infusion is consistently found in patients with severe LAD stenosis. 39 Three main mechanisms may be proposed to explain, isolated or in combination, why coronary flow cannot increase or may actually drop during adenosine infusion in severe stenoses: (1) In extremely tight stenoses, the microvascular reserve may already be exhausted at rest, because of maximal peripheral vasodilation, and cannot increase any further under stress; (2) An incompletely calcified coronary stenosis may maintain some degree of elasticity and may collapse during adenosine infusion 37,38 for a drop in intraluminal distending pressure induced by flow acceleration at the stenosis site (Venturi effect); (3) Pre-stenotic collaterals may open at stress, stealing blood from the ischaemic territory to perfuse other less jeopardized segments.58

23 Other authors have postulated that a relative increase in systolic velocity at rest is a marker of severe stenosis. 40 Further studies are needed to confirm the diagnostic value of this parameter, which has the limits described above for systolic flow, but the advantage of being obtained with a simple resting exam. CHRONIC TOTAL OCCLUSION Reverse diastolic flow at rest, reflecting retrograde filling of the artery by collaterals, is a very specific marker of coronary occlusion 41 but it unfortunately has a low sensitivity, since collaterals may perfuse the vessel either retrogradely or anterogradely. The collateral flow is routinely evaluated at rest with coronary angiography 42 but the predictive role of this method is uncertain. Conversely, the response of collateral flow to stress, which can be measured by intracoronary and transthoracic Doppler ultrasound, may add useful prognostic information. In his experience, according to Voci et al, it is feasible to measure CFVR in the PD in around 50% of the patients regardless of its origin from the right or circumflex coronary artery,12 but others have reported higher figures. 15 The lower success rate of imaging the PD compared to the LAD (feasibility 98%) depends on two factors: (1) The PD runs deep into the chest (7 8 cm) while the LAD is more superficial (<2 cm); (2) The PD runs close to the right ventricular inflow tract and to the mid-cardiac vein, which generate strong and disturbing diastolic and systolic flow signals. Adenosine-induced hyperventilation dedicated transducer has been designed for the LAD, whereas the PD is studied with a conventional imaging of the PD can be improved in several ways: (1) The use of ultrasound contrast agents improving the signal-to-noise ratio; (2) The use of specific A2A adenosine receptor agonists reducing side effects as hyperventilation; (3) The design of specific probes and software; (4) Reducing the heart rate to minimize wall motion artifacts on Doppler sampling.

24 Additional piece of information in the Doppler spectrum: the intensity of the reflected signal. Doppler intensity can be used to detect coronary vasomotion: it may decrease during handgrip in patients with coronary artery disease whereas it may increase or remain unchanged in normals. ROLE FOR THE MICROCIRCULATION Transthoracic coronary Doppler ultrasound has been used to study the impact on microvascular flow in a number of settings known to, or suspected of, altering microvascular flow, such as coronary stenting,44 remote coronary artery disease, sex hormones, cigarette smoking,20 left ventricular hypertrophy,22 diabetes and ageing With regard to remote microvascular alteration in focal CAD, we have found that CFVR in the angiographically normal coronary artery is never affected by remote coronary stenosis, AMI, or stenting. 55 These findings confirm that focal factors in each territory are the major determinants for CFVR, and impaired CFVR one region is not a general phenomenon of the coronary circulation. MONITORING THE CHANGES OF CFR IN THE EARLY, POST-PTCA PERIOD TO DETECT ARTERY OCCLUSION. Microvascular stunning due to microembolization,thrombogenicity (by thrombin release) and vasoconstriction (by endothelin release),and temporary reactive hyperemia, a state with high postischemic baseline flow velocity, masks normal reserve. Invasive CFR is obtained after multiple balloon inflations, injection of contrast agent and administration of vasoactive drugs that may produce immediatepost-procedural vasomotion instability.. Early reoclussionof the coronary artery is another complication after PTCA detectable by transthoracic Doppler echocardiography. SERIAL CFR EXAMINATION AFTER PTCA TO PREDICT RESTENOSIS Pierre Legalery et al showed that, One-year clinical follow-up demonstrated that patients left with medical treatment alone had a similar outcome to those submitted to revascularization and

25 concluded that subset of patients in whom the decision to revascularize contradicted the FFR results had less favourable event-free survival. Detection restenosis is feasible in mid- and long-term follow-up to monitor restenosis 37,38. The decrease of CFR <2 during follow-up was proposed as a sensitive and specific predictor of restenosis 25. This method may be complementary to exercise test, or may be its substitute if patients are unable to perform adequate exercise test. Besides CFR measurements distally to the stenosis, other methods have been been developed to detect restenosis after PTCA.. CORONARY STENTING AND CFR: CFR may normalize in 80 percent of patients after stenting, corresponding to improved lumen area as the mechanism responsible for improved coronary blood flow. The remaining 20 percent of patients with widely patent stents had impaired CFR (<2.0) attributed to microvascular disease and/or transient emboli from PCI. A low postprocedural CFR has been associated with a worse periprocedural outcome. FFR after stenting also predicts adverse cardiac events at follow-up. FFR immediately after stenting was an independent variable related to all adverse cardiac events. The event rate was 5 percent in patients in whom FFR normalized, 6 percent in patients with poststent FFR between 0.90 and 0.95, and 20 percent in those with FFR less than In patients with FFR less than 0.80, the event rate was 30 percent POSTINFARCTION CFR ASSESSMENT Ueno et al. showed that the decreased CFR <1.5 was identified to predict an increase in left ventricular volume (remodeling) after myocardial infarct reperfusion. A significant negative correlation was found between CFR and progression of left ventricular dilatation at 6-month follow-up. Colonna et al has shown that preconditioning due to pre infarction angina had a protective role on microvascular function as demonstrated by CFR preservation (>2.5) after myocardial infarction. CORONARY GRAFTS

26 It is very easy to measure flow in the left and right internal mammary arteries both at the origin 46 and at the level of the suture over the LAD 1,2,with important perioperative and follow-up information on the functional status of the graft. For saphenous vein grafts it is possible to measure flow at the level of the suture over the LAD. ASSESSMENT OF CORONARY GRAFT PATENCY Chirillo F, et al showed the identification rate for mammary artery grafts was 100%, for saphenous vein grafts to LAD coronary artery 91%, for the vein grafts to the right coronary artery 96% and for the vein grafts to circumflex artery 90%43. CFR <1,9 had 100% sensitivity, 98% specificity for mammary artery graft stenosis. CFR <1,6 had 91% sensitivity, 87% specificity for significant vein graft stenosis. ABSOLUTE VOLUMETRIC FLOW VERSUS FLOW VELOCITY MEASUREMENT OF CFR Only Hozumi et al. 19 achieved a very high feasibility of coronary flow imaging in their first study, i.e. 94%. Limitation may be minimized by using echo-contrast agents enhancing Doppler signal intensity, which are however expensive. With regard to cost-effectiveness balance, it was calculated that using 90-s noncontrast/adenosine vasodilator approach, the cost of the test was 14 times less expense than the 7-min contrast-enhanced approach. DIFFUSE ATHEROSCLEROSIS. Coronary arteries without focal stenosis are generally considered non-flow limiting. A diffusely diseased atherosclerotic coronary artery can be viewed as a series of branching units diverting and gradually distributing flow and reducing pressure longitudinally along the conduit. In such a vessel, a reduced CFR is not associated with any single location of stenotic pressure loss.. PITFALLS AND TROUBLE-SHOOTING CFR must be measured distally to stenosis, because erroneous CFR assessment at stenosis site is underestimated due to increased baseline flow velocity. In addition, the flow in the LAD branches

27 could be erroneously interpreted as flow in LAD main trunk. PIONEER WORKS OF NON INVASIVE ASSESSMENT OF CFR TO PREDICT LAD STENOSIS BY TTCDE WITH ANGIOGRAPHIC COORELATION: In chronological order, Lance Gould first established coronary blood flow velocity reserve can be measured by transthoracic ultrasound in his experimental works on effects of coronary stenoses on coronary flow reserve and resistance, and in hi s seminal work of physiologic basis for assessing severe coronary stenosis: instantaneous flow response and regional distribution during coronary hyperemia as measures of coronary flow reserve. Later, Fusejima reported that it was possible to measure coronary flow velocity in the midportion of the LAD with two-dimensional Doppler echocardiography, in the earlier studies with 65% success rates. Subsequent works by Voci in more than 1000 patients he established safety of adenosine induced vasodilation. Hozumi revealed that transthoracic CFR evaluation is useful in predicting restenosis after PCI.. Matsumura suggested Cut-off value of coronary flow velocity reserve by transthoracic Doppler echocardiography for diagnosis of significant left anterior descending artery stenosis in patients with coronary risk factors Transthoracic Doppler echocardiography is noninvasive, relatively inexpensive and widely used in the clinical setting, and can be used for serial studies in echocardiographic laboratories. Several studies have reported that CFV can be measured by visualizing LAD using transthoracic two-dimensional and Doppler echocardiography with a high-frequency transducer. It has been also shown that CFV in the distal LAD can be measured at high success rate by TTDE under the guidance of color Doppler flow mapping, and assessment of CFVR in the LAD by this noninvasive technique is useful in the diagnosis of significant LAD stenosis.

28 MATERIALS AND METHODS STUDY PATIENTS We have selected 59 patients who underwent coronary angiography for the evaluation of coronary artery disease, for chronic stable angina. They were included in this study after strictly adhering to study protocol. EXCLUSION CRITERIA Unstable angina Congestive heart failure Atrial fibrillation Previous coronary bypass graft surgery Diabetes mellitus Severe chronic obstructive pulmonary disease, or bronchospasm II III degree atrioventricular block Patients with short PR intervals Clinical history or ECG signs of a previous myocardial infarction, Evidence of primary myocardial or valvular heart disease. Uncontrolled hypertension. As the microvascular dysfunction in many of situations listed above, especially diabetic retinopathy and unstable angina, may cause alteration in CFVR independent of coronary stenosis, we carefully excluded those patients from the study. The entire patients who were included in the study were evaluated on the basis of proforma. Detailed history with special focus on cardiovascular risk factors were obtained.. Their treatment history was noted. All were submitted to thorough physical examination, routine

29 biochemical and hematological tests, resting ECG and Treadmill Exercise stress testing with bruce protocol. TWO DIMENSIONAL ECHOCARDIOGRAPHIC MEASUREMENTS OF LV FUNCTION AT BASELINE Before CFVR measurements by TTDE, we measured septal and LV posterior wall thickness at end diastole by two-dimensional echocardiography. LV volume measurements were performed according to the recommendation of the American Society of Echocardiography. Apical two- and four-chamber views were obtained at baseline. End-diastolic and end-systolic LV volumes and Ejection fraction were computed by use of modified Simpson's method.. Furthermore, we assessed regional wall motion at rest on the basis of 16 segments of the LV as recommended by the American Society of Echocardiography. No patient had evidence of LV hypertrophy (septal or posterior wall thickness at diastole >12 mm) on echocardiographic examination, as LVH itself becomes an exclusion criteria for the study. Then TTCDE for measuring CFR was carried out for all patients before coronary angiography.those who had lesions in the LAD were included in this study. COLOUR DOPPLER ECHOCARDIOGRAPHIC STUDIES TWO dimensional and M-mode measurements were obtained with patients in left lateral position using an ALOKA SSD4000 phased array system equipped with tissue Doppler and harmonic imaging technology with Doppler frequency of 2.5 to 3.8 mhz. Later it was switched over to 5mhz to 7.5mhz, When optimal images not obtained in individual patients. The acoustic window was around the midclavicular line in the fourth and fifth intercostal spaces in the left lateral decubitus position. First, the left ventricle was imaged in the long-axis cross section, and then the ultrasound beam was inclined laterally. The color gain was adjusted to provide optimal images. Next, coronary blood flow in the distal portion of the LAD was searched under the guidance of color Doppler flow mapping. With a sample volume (1.5 or 2.0 mm wide) positioned on the color

30 signal in the LAD, Doppler spectral tracings of flow velocity in the LAD were recorded by pulsed doppler. The spectral Doppler of the LAD flow showed a characteristic biphasic flow pattern with a larger diastolic component and a small systolic one. All studies were continuously recorded on 1/2 inch super- VHS videotape for off-line analysis. CFVR MEASUREMENTS BY TTCDE We first recorded baseline spectral Doppler signals in the distal portion of the LAD. Adenosine was administered (140 µg kg-1 min-1 IV) for 2 minutes to record spectral Doppler signals during hyperemic conditions. All patients had continuous heart rate and ECG monitoring. Blood pressure was recorded at baseline, every minute during adenosine infusion, and at recovery. Measurements were performed off-line by tracing the contour of the spectral Doppler signal using the computer incorporated in the ultrasound system. MDV and PDV were measured at baseline and peak hyperemic conditions. PSV was also measured at baseline and peak hyperemic conditions. An average of the measurements was obtained in three cardiac cycles. Density of Doppler spectrum was also noted in all patients both at baseline and after adenosine. CFR was defined as the ratio of hyperemic to basal peak diastolic coronary flow velocity (CFR PDV) and the ratio of hyperemic to basal mean diastolic coronary flow velocity (CFR MDV). Normal CFR was defined as >2.0 on the basis of previous studies that evaluated flow velocities in the distal LAD CORONARY ANGIOGRAPHY Reason for coronary angiography was evaluation for coronary artery disease, for chronic stable angina. Coronary angiogram done in the Siemens mobile unit cath lab in our hospital, and Philips mounted lab at GH. Coronary angiograms were done through right femoral approach using modified seldinger technique. Low osmolar nonionic contrast agent (omnipaque) was used. Coronary angiography was